The immune response to chronic leishmaniasis in humans is not well understood. These clinical diseases are not easily classified as polarized T helper 1(Th1) or Th2 immune responses. In contrast, murine infection with Leishmania major has been extensively studied as an in vivo model of Th1 or Th2 development. This proposal is based on the finding that CH3 and C57BL/6 mice are resistant to infection with the parasite Leishmania major but they are susceptible to infection with the related parasite L. amazonensis. This susceptibility is manifested by a single persistent non-healing cutaneous lesion, which is accompanied by a poor cellular immune response. We feel that the chronic L. amazonensis infection in these mice may more accurately reflect the immune response seen in chronic leishmaniasis of humans. The differences in the immune response to these two related parasites provide an excellent opportunity to study factors critical to host resistance and susceptibility, while eliminating host genetics as a variable. Resistance to L. major is is mediated by the development of a CD4+ Th 1 response, which is initiated by the cytokines IL-12 and IFN-g. The preliminary data demonstrates t during L. amazonensis infection endogenous IL-12 is reduced, the IL-12 receptor (IL-12R) is decreased on CD4+ T cells and the lymph node cell population is unresponsive to IL-12. The absence of these mediators of Th1 development correlate with a remarkable finding that exogenous IL-12 is unable to promote an effective Th1, cell-mediated, immune response towards L. amazonensis. Our hypothesis is that a Th1 response would resolve L. amazonensis infection and that the L. amazonensis prevents cell-mediated immunity by inhibiting IL-12 responsiveness. The experiments in this proposal will determine if the loss of functional IL-12R expression on the CD4+ T cell population and loss of IL-12 responsiveness of these cells is a primary factor in the development of a chronic infection. Since IL-4KO mice are also resistant to the Th1 promoting effects of exogenous IL-12 after L. amazonensis infection, experiments are proposed to determine if regulation of the IL-12R in vivo is independent of IL-4 and influenced by endogenous TGF-b. An active role of the parasites for the suppression of the Th1 response will be tested by the elimination of the parasites in vivo and it will be determined if there is a differential regulation of the CD4+ T cell population with the different stages of the infectious parasite. In addition, the T cell response will be characterized and it will be determined if differences in costimulation can modify the expression of the IL-12R and regulate IL-12 responsiveness on the antigen specific T cell population. Potential defects in T cell cytokine production and proliferation will also be assessed. Since dendritic cells become activated after L. major infection, the dendritic cell response to L. amazonensis will also be examined. L. amazonensis infected dendritic cells will be assessed for activation, IL-12 production, and their ability to promote T cell proliferation and regulation of the IL-12R. The efforts of this proposal will have direct application to the development of more effective immunomodulatory regimes for Leishmania and other infectious diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Tropical Medicine and Parasitology Study Section (TMP)
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Wali, Tonu M
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Iowa State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Ramer-Tait, Amanda E; Petersen, Christine A; Jones, Douglas E (2011) IL-2 limits IL-12 enhanced lymphocyte proliferation during Leishmania amazonensis infection. Cell Immunol 270:32-9
Gibson-Corley, Katherine N; Boggiatto, Paola M; Mukbel, Rami M et al. (2010) A deficiency in the B cell response of C57BL/6 mice correlates with loss of macrophage-mediated killing of Leishmania amazonensis. Int J Parasitol 40:157-61
Boggiatto, Paola Mercedes; Jie, Fei; Ghosh, Mousumi et al. (2009) Altered dendritic cell phenotype in response to Leishmania amazonensis amastigote infection is mediated by MAP kinase, ERK. Am J Pathol 174:1818-26
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Mukbel, Rami; Petersen, Christine A; Jones, Douglas E (2006) Soluble factors from Leishmania major-specific CD4+T cells and B cells limit L. amazonensis amastigote survival within infected macrophages. Microbes Infect 8:2547-55
Ramer, Amanda E; Vanloubbeeck, Yannick F; Jones, Douglas E (2006) Antigen-responsive CD4+ T cells from C3H mice chronically infected with Leishmania amazonensis are impaired in the transition to an effector phenotype. Infect Immun 74:1547-54
Vanloubbeeck, Y; Ackermann, M R; Jones, D E (2005) Late cutaneous metastases in C3H SCID mice infected with Leishmania amazonensis. J Parasitol 91:226-8
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